Advanced age is not the decisive factor in chemotherapy of small cell lung cancer: a population-based study

Objective: There is limited research on the impact of chemotherapy on the prognosis of different age group patients with small cell lung cancer (SCLC). The aim of this study was to explore the impact of chemotherapy on survival prognosis of elderly patients with SCLC. Methods: Based on the Surveillance, Epidemiology and End Results (SEER) database, 57,460 SCLC patients between 2004 and 2015 were identified and divided into a ≤ 80 years group (n = 50,941) and a >80 years group (n = 6,519). Confounding factors were controlled by propensity score matching (PSM) analysis. Kaplan Meier (KM) analysis was performed to determine the impact of chemotherapy on overall survival (OS) and lung-cancer specific survival (LCSS) of the patients. Other variables that could affect survival of SCLC patients were also examined by COX analysis. Results: KM analysis showed that both OS and LCSS were improved in chemotherapy group compared to those in non-chemotherapy group (log rank P < 0.001) in both age groups after PSM. Cox analysis demonstrated the survival benefit of chemotherapy in both ≤ 80 years group (OS: HR 0.435; 95% CI 0.424–0.447; LCSS: HR 0.436; 95% CI 0.424–0.448) and >80 years group (OS: HR 0.424; 95% CI 0.397–0.451; LCSS: HR 0.415; 95% CI 0.389–0.444). Additionally, the following parameters had a negative impact on survival of elderly patients: male sex, tumor location in main bronchus, increased stage, bilateral tumor, no surgery or radiation, and lower median household income. Conclusions: Elderly patients with SCLC should be encouraged to receive chemotherapy provided their general conditions permit.

AGING at diagnosis [5], and there is an increasing trend in the proportion of SCLC patients in the age group older than 75 years according to a study from Hebei, China [6].
Over the past three decades, chemotherapy has provided considerable survival benefits for SCLC patients [7], and remains the standard treatment for first-and second-line management of SCLC [8]. Immunotherapy also plays an important role in patients with relapsed SCLC [8]. There have been many clinical trials on immune checkpoints inhibitors (ICIs), tumor vaccines, antigenic targets, and adoptive cellular immunotherapy in SCLC, but the results have been somewhat disappointing so far [9]. Treatment planning and decision mainly depend on the cancer TNM staging system and the Veterans Administration Lung Study Group (VALG) staging system, according to the National Comprehensive Cancer Network Clinical Practice Guidelines for SCLC, the Chinese Society of Clinical Oncology Lung Cancer Guidelines, and the European Society for Medical Oncology Clinical Practice Guidelines for Metastatic SCLC [10]. With the overall population life expectancy improving, treatment for elderly patients has aroused increasing attention. Given the performance status (PS) of the elderly and the associated comorbidities and toxicity, some oncologists are not inclined to using chemotherapy in elderly patients with SCLC [11]. So, whether chemotherapy is beneficial to elderly patients needs to be further confirmed. Several retrospective cohort studies exploring the relationship between age and treatment choice have defined elderly patients as age ≥ 65 [12,13], ≥ 70 [14,15] or ≥ 75 years old [11,16]. There is limited research on patients > 80 years old, much less in elderly SCLC patients older than 80 years. A recent single center retrospective study evaluated the survival outcome associated with the treatment strategies in 56 cancer patients aged over 80 years, but only 7 of them were SCLC patients [17]. The aim of present study is to explore the impact of chemotherapy on survival prognosis of elderly patients with SCLC using the Surveillance, Epidemiology and End Results (SEER) database.

Data source
We performed this study to verify the relationship between chemotherapy and the survival prognosis of SCLC patients of different ages. All the data were based on the Surveillance, Epidemiology, and End Results (SEER) database, which was established in 1973 and collects information on cancer incidences and survival in the United States (US), covering 17 population-based cancer registries, accounting for about 28% of the current US population [18]. From 74,294 SCLC patients initially identified from the  SEER database between 2004 and 2015, we included  57,460 patients for final analysis after excluding 13,544  patients without first malignant primary indicators, 167  with unknown survival months and 3,123 with incomplete data according to the inclusion and exclusion criteria (Figure 1). They were divided into two age groups: ≤ 80 years group (n = 50,941) and >80 years group (n = 6,519), and each group was further divided into chemotherapy group (n = 37,136 for ≤ 80 and 2,774 for >80 years) and non-chemotherapy group (n = 13,805 for ≤ 80 and 3,745 for > 80 years).

Covariates
Baseline clinical characteristics including median age at diagnosis, gender, race, region, year of diagnosis, primary site, grade, laterality, stage, radiation, surgery, marital status, education level and median household income were collected.

Statistical analyses
Continuous variables were compared using t-test, and categorical variables were compared using chi-square. Potential deviation between chemotherapy and nonchemotherapy groups was controlled by propensity score matching (PSM) analysis. Kaplan-Meier (KM) analysis and the log rank test were applied to compare overall survival (OS) and lung-cancer specific survival (LCSS) between patients with or without chemotherapy. To study whether other variables could affect survival of SCLC patients, COX analysis was performed in each group. Statistical significance was set at a two-tailed P value < 0.05. All analyses were performed with IBM SPSS version 25.0.

Study cohort characteristics
Demographic and clinical characteristics of the patients are included in Table 1. Among these, 50,941 were ≤ 80 years old and 6,519 were >80 years old, and their median age at diagnosis was 65 years (interquartile range, 59-72 years) and 83 years (interquartile range, 81-85 years) respectively. Both groups of patients were distributed roughly equally by gender (men 50.4%, women 49.6% in ≤ 80 years group; men 47.0%, women 53.0% in >80 years group). Most patients were Caucasian (86.9% in ≤80 years group; 87.8% in >80 years group), and from the East (50.8% in ≤80 years group; 41.6% in >80 years group) or Southwest (36.5% in ≤80 years group; 45.1% in >80 years group), only a few (0.2% in ≤80 years group; 0.1% in >80 years group) were living in the Northwest. Most patients did not receive surgical treatment (96.8% in ≤80 years group; 98.0% in >80 years group) or radiotherapy (51.1% in ≤80 years group; 74.4% in >80 years group). Patients in the early stage, married, treated with radiation but not surgery and had better education were more likely to receive chemotherapy. About 43% of the elderly patients in our study received chemotherapy. Most (73%) of the younger patients chose chemotherapy ( Table 1). The proportion of SCLC patients choosing chemotherapy did not vary significantly with the year of diagnosis ( Figure 2).

Comparison of survival curves between chemotherapy group and non-chemotherapy group
Enrolled in the study were 27,486 patients ≤ 80 years old and 4,550 patients >80 years old after propensity score matched analysis. KM analysis demonstrated improved OS and LCSS in patients of chemotherapy group compared to patients of non-chemotherapy group,  with the survival curves showing statistically significant differences (log rank P < 0.0001) in both ≤ 80 years group and > 80 years group (Figure 3).  (Tables 2 and 3; Figure 4). The following parameters had a negative impact on survival of patients in ≤ 80 years group: Caucasian, male sex, later year of diagnosis, older age, north region, tumor location in main bronchus, increased stage and grade, bilateral tumor, no surgery or radiation, separation, lower median household income and poorer educated, while the following parameters had a negative impact on survival of patients in > 80 years group: male  sex, tumor location in main bronchus, increased stage, bilateral tumor, no surgery or radiation, and lower median household income.

DISCUSSION
The results of our study demonstrated the benefit of chemotherapy in both young and elderly SCLC patients. Although chemotherapy could benefit OS and LCSS regardless of age, patients older than 80 years tended to reject chemotherapy compared with patients younger than 80 years. Besides, the results of our COX analysis showed that male sex, an increased stage and grade, and no surgery or radiation were associated with worse prognoses. In < 80 years group, Caucasian patients who were diagnosed late or at an older age tended to have worse prognoses.
More studies have paid increasing attention to the relationship between chemotherapy and survival of   [20]. A study from the Japanese Joint Committee of Lung Cancer Registry [21] reported that OS of their 228 SCLC patients aged > 75 years who received second-line chemotherapy was 13.9 weeks, which was significantly higher than 7.5 months in those who received supportive care alone in a previous randomized controlled study [22]. A meta-analysis recruiting 14 relevant randomized clinical trials from the Medline and Cochrane databases reported that the 1-year OS improved from 30% to 39% and the 2-year OS improved from 10% to 14% in SCLC patients who received maintenance chemotherapy [23]. Several previous studies concluded that patients of advanced age tended to reject chemotherapy, which is consistent with our study. By reviewing a number of retrospective studies, Deppermann et al. [24] concluded that elderly patients were often offered only suboptimal or no treatment. Researchers from the British Columbia Cancer Agency carried out a retrospective review on 174 patients with SCLC between 1991 and 1999, and categorized them into three age groups: < 65 years (n = 55), 65-74 years (n = 76), and ≥ 75 years (n = 43). The results displayed that elder patients tended to fail to complete an "optimal" course (intravenous regimens, more than 85% total doses, 4+ cycles, and less than 2 weeks total treatment delays) of first-line chemotherapy (P < 0.05), and patients >65 years were less likely to administer second-line chemotherapy (P < 0.05) [16]. In the light of a recently published retrospective analysis of SCLC patients at IPO-Porto, Portugal's largest oncology hospital, the median age of patients who received platinum doublet chemotherapy was lower than the respective full populations (LS-SCLC: 64 years vs. 70 years; ES-SCLC: 63 years vs. 64 years), suggesting that age may affect the patient's decision whether to receive chemotherapy [25]. Stacey et al. [11] reported that PS and the presence of comorbidities were the most common factors that affected clinical oncologists not to recommend chemotherapy, and most patients rejected chemotherapy mainly because of their concerns about toxicity. Our COX analysis also demonstrated that surgery and radiation were positively associated with better survival, which is consist with other recent studies [26][27][28][29]. In a retrospective analysis of 366 SCLC patients receiving chemotherapy or chemoradiotherapy [28], Kanaji [19].
Our study investigated a large cohort of 57,460 SCLC patients from real world data. Although many other studies have also addressed the effect of chemotherapy on the survival prognosis of SCLC patients [16,17,19,20,22], they were mostly based on limited sample sizes, and there have been few investigations on the prognosis of different age subgroups. Given aging of the population, patients older than 80 years will account for a greater proportion. Therefore, the results of our study may provide useful information for clinical oncologists and elderly patients in choosing treatment options. Additionally, we also analyzed the impact of other factors on patient survival, which may also guide patient management. However, several deficiencies in our research need to be mentioned. Despite the large sample size of the SEER, the smoking status and PS are not available in the database, knowing that the former is strongly associated to SCLC [30,31], and the latter has also proved to be related to the prognosis of SCLC patients [32]. It is possible that patients who smoke or have a low PS score were included in the nonchemotherapy group, which may induce biases in the results. Concurrently, reasons for not choosing chemotherapy, or potential factors affecting the receipt of chemotherapy, such as the nutritional status, cognitive function and geriatric syndrome, are not included in the SEER, either. These limitations need to be refined in future validation using data from hospitals, or randomized controlled trials.

CONCLUSIONS
To conclude, chemotherapy is a beneficial choice for patients with SCLC over 80 years old, although elderly patients are less likely to receive chemotherapy. Age should not be the main basis for deciding whether to receive chemotherapy or not.

AUTHOR CONTRIBUTIONS
H.R., A.M., and S.Z. designed the study; H.R. and S.X. were responsible for collection and assembly of data; S.X. revised it critically for important intellectual content. All authors contributed to data analysis and interpretation have reviewed the final version.